Abstract Mood disorders are highly disabling and affect 60 million Americans. Individuals experiencing mood symptoms and comorbid conditions (e.g., anxiety) also experience a decrement in their ability to use working memory in everyday life. Understanding neurobiological characteristics of cognitive and emotional dysfunction in distinct psychiatric disorders remains challenging because multiple psychiatric disorders share common patterns of disruption in brain functioning supporting cognitive and emotional processes. We propose to use a dimensional (RDoC) approach to analyze already collected functional magnetic resonance imaging (fMRI) to identify aberrant neurobiological mechanisms of continuous constructs of depression (ranging from no depression to sub-threshold depression to syndromal depression) and mania (ranging from no mania to sub-threshold mania to syndromal mania) symptoms and their relationship to working memory dysfunction. This 2-year study will merge clinical, behavioral and neuroimaging data from five studies (PI: Phillips) and analyze the merged large dataset across diagnoses using a dimensional approach. We will determine the relationship between behavioral and neural correlates of working memory and current and life-time symptoms of depression, mania, and comorbid anxiety in youth (8-17) and adults (18-45). We will validate these findings using an independent dataset (Aim 1). We will also examine how longitudinal improvement/worsening of depression, mania and comorbid anxiety symptoms over the 6-month period affects adult subjects? ability to perform difficult working memory tasks and engage the working memory circuitry during those tasks across diagnoses (Aim 2). The development of working memory in youth involves improvement of the ability to recruit working memory circuitry during working memory tasks. This maturation process may be disrupted by worsening of mood and anxiety symptoms. We will use longitudinal data to map working memory circuitry functioning across a range of ages and developmental time frames, and across the range of syndromal and non-syndromal depression, mania and comorbid anxiety across diagnoses (Aim 3). The proposed research will lay the foundation for understanding neural mechanisms underlying longitudinal trajectories in depression, mania and anxiety spectrum symptoms. It will provide neurobiological targets to help guide personalized treatment and facilitate development of new interventions to alleviate working memory dysfunction in affected individuals.